New Origins for Organs

Organs grown from animal cells offer new hope



In a test of a potential new treatment for diabetes, a transplant of pig pancreas cells begins producing globules of insulin (highlighted by arrows).

On average, seven U.S. patients die every day while waiting for a transplant. Organs grown from animal cells could provide an almost limitless alternative.







GROWING NEW ORGANS INSIDE THE BODY to take the place of damaged or diseased organs might seem like science fiction, but researchers at Washington University School of Medicine recently pushed it into the realm of science fact.

Marc R. Hammerman, MD, the Chromalloy Professor of Renal Diseases in Medicine and head of the renal division at Barnes-Jewish Hospital, and Sharon A. Rogers, MS, research instructor in medicine, had previously shown that they can transplant embryonic rat tissue into adult rats and coax the tissue’s growth into fully functional kidneys.

In a groundbreaking experiment reported this past summer, Hammerman and Rogers put the technology to a crucial test: Could the new kidneys sustain life in the absence of the rats’ original kidneys?

As Hammerman and Rogers had planned, the new kidneys kept the rats alive for seven to eight days. Experts in organogenesis, a new discipline focused on growing replacement organs inside the body, are likely to one day look back on the accomplishment as one of their field’s Kitty Hawk moments.

“Seven to eight days may not seem like very long,” Hammerman notes, “but I hope what we have done is akin to the Wright brothers achieving heavier-than-air flight for just 59 seconds on their first try, long enough to change the course of history. I believe it’s just as significant to show that life can be preserved by a newly grown kidney for several days. We think that our finding will change the course of medical history.”

Marc R. Hammerman, MD, reviews organogenesis
research images.

If successful in the years of animal and human trials to come, the new approach could ease two of the greatest obstacles doctors regularly confront in treating patients with failed organs: the drastic shortage of human donor organs and the relentless threat of immune system rejection of transplanted organs.

The need for kidney transplants is so great — and the supply of human replacement organs so limited — that, on average, seven U.S. patients die every day while waiting for a transplant. Organs from animals such as pigs could provide an almost limitless alternative. However, their use in humans is prevented by severe humoral rejection, an immune response humans mount against transplanted mature pig organs.

Hammerman theorized that the use of embryonic precursors of animal organs, rather than the mature organs themselves, would avoid the problem of humoral rejection. In addition, he speculated that such transplants might require less use of immune suppression drugs, an essential step in human organ transplants that makes patients vulnerable to infections.

His hunch about reduced need for immune suppression paid off early this year in his second major line of organogenesis research, focused on treating diabetes.

Hammerman’s animal tissue donor of choice is the pig. Pig kidney size and function are similar to human kidneys, and human diabetes has long been successfully treated with pig insulin.

The tissues Hammerman works with are groups of embryonic cells known as primordia. Unlike stem cells, organ primordia cannot develop into just any cell type — they are locked into becoming a particular cell type or one of a set of cell types that make up an organ.

“For our kidney research program, being locked into forming a kidney is very important,” Hammerman says. “The kidney is structurally and functionally quite complex; it would be virtually impossible to program cells to grow into a functional kidney if the cells didn’t already know how to do it.”

Hammerman and Rogers are currently working to perfect pig-to-rat kidney primordia transplants. If they can extend life in rats with newly grown pig kidneys doing all the “kidney work,” the next steps are pig-to-primate and then pig-to-human transplants.

Scientists surgically removed one of this rat’s kidneys and replaced it with a transplant of embryonic kidney precursors, called primordia, now growing into a new kidney inside the rat.

Diabetic patients hoping to be treated via insulin-producing islet cell transplants confront an even scarcer supply of available donor tissue than kidney patients, Hammerman notes.

“For one thing, you can’t take a pancreas out of a living patient like you can a kidney,” he says. “Also, one pancreas doesn’t give you enough islets to treat a diabetic patient.”

Doctors need to process the pancreas to get to the islets, but that processing batters the cells, lowering the rates at which they can successfully engraft.

Pig pancreas primordia are relatively easy to isolate. As they grow, they “know” how to divide into just the right number of insulin-producing cells to precisely regulate glucose levels in diabetic hosts.

“We have never had a problem with too much insulin being produced,” says Hammerman.

In a study published early this year, Hammerman and Rogers had given two groups of diabetic rats pig pancreatic primordia transplants, but they only gave one group drugs to suppress hostile immune system responses. They thought the transplants wouldn’t engraft in the rats not given immune suppression.

When the transplants grew and functioned well in both immune-suppressed and non-immune-suppressed groups, the focus of the study changed to the rats that had not received immune suppression. The transplants restored the rats’ levels of blood glucose to normal and also restored their ability to gain weight.

“The unusual way the embryonic pancreas develops after transplantation from one species into another appears to make it ‘invisible’ to the host’s immune system,” says Hammerman. “Now we have the theoretical possibility of being able to transplant pancreatic primordia and not having to bother with immunosuppression at all.

“That’s a long shot, but I have reason to hope it will apply for pig embryonic pancreas transplanted into primates and even into humans.”

Hammerman hopes to see human trials for the techniques he’s developing.

“By the middle of this century, medical textbooks will have sections devoted to therapies based on growing new organs,” he confidently predicts. “I want our work to be the first chapter.”